JP6974265B2 - A composition containing an energy absorbing material for hair follicle delivery and a method for delivering the same. - Google Patents

Description

Related Application Data This application is based on US Provisional Patent Application No. 61 / 636,381 filed on April 20, 2012, and US Practical Patent Application No. 13/789, filed on March 7, 2013. Claim the benefit of the specification 575. The entire contents of the aforementioned patent application are incorporated herein by reference.

This application may include subject matter relating to what was disclosed and claimed in U.S. Patent Application Publication No. 2012/0059307A2 published March 8, 2012, the entire contents of which are hereby incorporated by reference. It will be used.

Acne vulgaris is a hair follicular skin disease characterized by the appearance of acne, papules, nodules, and cysts. Acne is a condition in which hair follicles are blocked by keratin plugs. Open pimples with visible keratin plugs become "black acne" and closed pimples become "white acne", which often progress to inflammatory papules, nodules, and cysts. The presence of bacteria in the hair follicles attracts white blood cells to the hair follicles, which can lead to inflammatory reactions such as those seen as papules (red acne), pustules, and nodules. Acne can be mild with few acne or papules, or it can be highly inflammatory and leave ugly scars. There is a need for improved methods of treating or alleviating hair follicular skin disorders such as acne vulgaris.

As described below, the present invention relates to methods of treating or alleviating hair follicular skin disorders (eg, acne) of a subject (eg, human) and energy (eg, light) absorbing submicron particles (eg, silica core). Compositions containing nanoparticles including gold shells), and such particles used according to those methods, are delivered by topical application, for example, into hair follicles, sebaceous ducts, and / or sebaceous glands. Provide a method.

Accordingly, in one aspect, the invention is a method of treating or alleviating a subject's hair follicle skin disease, the step of topically applying a formulation comprising submicron particles containing a light absorbing material to the subject's skin; Stirring, acoustic vibration, ultrasonic waves, alternating suction and pressurization, or microjets to facilitate delivery of material into the skin's hair follicles, sebaceous glands, ground ducts, or funnels. Provided are a method comprising; a step of performing energy activation of submicron particles and thereby treating or alleviating a hair follicular skin disease of interest;

In another aspect, the invention is a method of improving the appearance of enlarged pores in a subject's skin, with the step of topically applying a formulation comprising submicron particles containing a light absorbing material to the subject's skin; Stirring, acoustic vibration, ultrasound, alternating suction and pressurization, or microjets to facilitate delivery of material to the skin's hair follicles, sebaceous glands, sebaceous glands, or funnels; submicron particles. Provided are a step of performing energy activation of the subject and thereby improving the appearance of enlarged pores in the skin of the subject; and a method comprising;

In yet another embodiment, the invention is a method of improving the appearance of a subject's greasy skin, comprising the step of topically applying a formulation comprising submicron particles containing a light absorbing material to the subject's skin; mechanical stirring, With the steps of alternating acoustic vibration, ultrasound, suction and pressurization, or facilitating the delivery of submicron particles to the skin's hair follicles, sebaceous glands, sebaceous glands, or funnels by microjets; Provided are a step of performing energy activation of the subject, thereby improving the appearance of the subject's greasy skin, and a method comprising;

Another aspect of the present invention is a method for permanently removing hair of a target, in which a step of locally applying a light absorbing material to the skin of the target and energy activation of the material are performed, whereby the hair is permanently removed. The process and the method including; are provided. In one embodiment, the hair is lightly pigmented or fine hair. In another embodiment, the method further comprises the step of topically applying a light absorbing material to the subject's skin and removing hair from the subject's hair follicles prior to energizing the material.

In another aspect, the invention is a method of treating hyperhidrosis by heat-damaging the eccrine glands or their surrounding areas, the step of topically applying a light absorbing material to the skin of a subject and the energy of the material. Provided are methods that include activation, thereby permanently removing the eccrine glands and treating hyperhidrosis.

In yet another aspect, the invention is a method of facilitating delivery of a light absorbing material to a target volume within the subject's skin to achieve a therapeutic effect, wherein a formulation comprising the light absorbing material is applied to the subject's skin. A step of topical application to allow the material to be delivered to the reservoir in the skin; delivery of the material into the target volume within the target skin by irradiating the skin with a first series of light pulses. A method comprising: exposing the light absorbing material to a second series of light pulses to heat the material and thermally damaging the target volume to achieve a therapeutic effect.

In yet another aspect, the invention is a method of facilitating delivery of a light absorbing material to a target volume within the subject's skin to achieve a therapeutic effect, wherein the formulation comprising the light absorbing material is topical to the subject's skin. The step of applying; the step of facilitating the delivery of the material to the reservoir in the skin by mechanical agitation; and the step of applying a series of low energy laser pulses with a duration of each pulse of 1 microsecond or less to apply the material. A step of facilitating the delivery of the material to the target volume within the skin by invading the target volume; the light absorbing material is exposed to a second series of low energy laser pulses to heat the material and heat damage the target volume. To provide a method including a step of achieving a therapeutic effect and;

Yet another aspect of the present invention is a method of treating or alleviating a hair follicle skin disease of a subject, wherein a preparation containing submicron particles containing a light absorbing material is locally applied to the skin of the subject; in the preparation. The process of facilitating the delivery of material from the skin into the hair follicles by acoustically generated microjets; the process of activating the energy of submicron particles and thereby treating hair follicle skin diseases; Provide a method to include.

In yet another embodiment, the invention is a method of treating or alleviating a subject's hair follicle skin disease, comprising exposing the subject's skin to a formulation comprising submicron particles containing a light absorbing material; to the hair follicles. A step of facilitating the delivery of material from the skin into the hair follicles by low frequency ultrasonically induced cavitation in the formulation near the surface of the adjacent skin; energy activation of submicron particles, thereby hair. Provided are steps of treating folliculous skin disorders and methods including;

Yet another aspect of the invention is a method of facilitating delivery of a light absorbing material to a target volume within the subject's skin by topically applying a formulation comprising the light absorbing material to the subject's skin so that the material is skin. A step of ensuring delivery to a reservoir within the target volume of the skin; and a step of facilitating the delivery of the material to the target volume within the target skin substantially in the transpilous route; a series of light absorbing materials. A method comprising the steps of heating a material by exposure to a light pulse to thermally damage the target volume to achieve a therapeutic effect;

In another aspect, the invention is a method of treating or alleviating a subject's hair follicle skin disease, the step of topically applying a formulation comprising particles of a light absorbing material to the subject's skin; primarily the corresponding hair follicle. To selectively facilitate the delivery of particles in the formulation into the sebaceous glands through the formulation, a step of causing acoustic cavitation in the formulation; and a step of irradiating the particles with light to treat folliculous skin disease; Provide methods including.

Another aspect of the invention is a method of treating or alleviating a subject's hair follicle skin disease, comprising the step of topically applying a formulation comprising submicron particles containing a light absorbing material to the subject's skin; Provided are methods comprising: delivering into one or more sebaceous glands via the transhair follicle route; and performing energy activation of submicron particles, thereby treating hair follicle skin disease.

Yet another aspect of the present invention is a method of treating or alleviating a hair follicle skin disease of a subject, wherein a preparation containing submicron particles containing a light absorbing material is locally applied to the skin of the subject; hair follicles. A step of facilitating the delivery of material into hair follicles by low frequency ultrasonically induced cavitation near the surface of the skin adjacent to the skin; using the heat generated by irradiating the submicron particles with light. , A step of treating or alleviating hair follicular skin disease adjacent to submicron particles;

The aforementioned method embodiments of the invention or other aspects of the invention described herein include a number of useful embodiments universally applicable to the methods of the invention described herein.

Thus, in one embodiment, delivery of the light absorbing material, eg, into the hair follicle, is facilitated by a microjet generated by ultrasonic waves in the pharmaceutical product.

In another embodiment, the submicron particles for energy activation include irradiating the submicron particles with light, thereby heating the particles.

In another embodiment, the submicron particles are within the sebaceous glands during irradiation. In one embodiment, the submicron particles are substantially completely within the sebaceous glands during irradiation. In another embodiment, the submicron particles are in the sebaceous gland duct during irradiation. In yet another embodiment, the submicron particles are substantially completely within the sebaceous gland duct during irradiation. In yet another embodiment, the submicron particles are within the funnel involved in hair follicular skin disease.

In certain embodiments, the light absorbing material in the formulation comprises a photoactive compound, a photodynamic therapy (PDT) prodrug or a PDT drug.

In one embodiment, the application of ultrasonic waves is performed at frequencies in the range of 20 kHz to 500 kHz. In another embodiment, the application of ultrasonic waves is performed at frequencies in the range of 20 kHz to 100 kHz. In yet another embodiment, the application of ultrasonic waves is performed at frequencies in the range of 20 kHz to 60 kHz. In yet another embodiment, the application of ultrasonic energy is performed at frequencies in the range of 30 kHz to 50 kHz.

In one embodiment, the ultrasonic output density is about 0.5-50 W / cm ² . In another embodiment, the peak-to-peak amplitude displacement of the ultrasonic horn surface is in the range of 0.5-30 microns.

In certain embodiments, the particles or light-absorbing material are sized to fit into or along the hair follicle pores. In one embodiment, the particles are formed to a size of about 1 micron to about 5 microns. In another embodiment, the particles are about 50 nm to about 250 nm in diameter. In yet another embodiment, the particles are nanoshells.

In another particular embodiment, the size of the submicron particles of the invention is selected to pass through the hair follicle and into the sebaceous glands of the hair follicle. In one embodiment, the hair follicle is a terminal hair follicle. In another embodiment, the hair follicle is a vellus hair follicle. In yet another embodiment, the hair follicles are sebaceous hair follicles.

In one embodiment, the submicron particle size is from about 0.01 micron to about 1.0 micron. In another embodiment, the submicron particle size is from about 0.05 micron to about 0.25 micron.

In one embodiment, the facilitation step further comprises selecting the properties of the ultrasonically generated microjet so that bubbles approximately the same size as the hair follicle pores are formed in the formulation. In another embodiment, the facilitation step further comprises selecting the properties of cavitation induced by low frequency ultrasound so that bubbles approximately the same size as the hair follicles are formed in the formulation.

In another embodiment, the ultrasonically generated microjets in the formulation are generated within about 50 to about 100 microns from the surface of the skin of interest.

In certain embodiments, delivery of the light-absorbing brain membrane is facilitated by an immersion cavitation step. In one embodiment, the accelerating step causes cavitation within about 50-100 microns from the surface of the skin. In another embodiment, the portion of the stratum corneum of the portion of the skin of subject that has undergone the delivery step remains intact.

In other specific embodiments, delivery, eg, delivery of the light absorbing material, in a substantially transhair follicle pathway, eg, into one or more sebaceous glands or hair follicles, is the surface of the skin adjacent to the hair follicle. It is facilitated by cavitation induced by low frequency ultrasound in the vicinity. In one embodiment, the induced cavitation occurs from about 50 microns to about 100 microns from the surface of the skin. In another embodiment, the properties of low frequency ultrasound are selected so that the stratum corneum remains intact with cavitation induced near the surface of the skin.

In one embodiment, the hair follicular disease being treated is hyperhidrosis. In certain embodiments, the facilitation step delivers particles into the eccrine gland via the eccrine gland duct.

In another embodiment, the hair follicle disease to be treated is acne vulgaris. In yet another embodiment, the hair follicular disease being treated is sebaceous hyperplasia. In yet another embodiment, the hair follicle disease to be treated is hirsutism.

In one embodiment, the submicron particles are coated with PEG. In another embodiment, the particles have an absorption peak at a wavelength of 700-1,100 nm. In another embodiment, the ratio of shell diameter to core diameter of submicron particles is from about 1.05 to about 2.0.

In another embodiment, the submicron particles are nanoparticles or nanoshells. In certain embodiments, the nanoparticles or nanoshells have a diameter of about 50 to about 300 nm (eg, 50, 75, 100, 125, 150, 175, 200, 250, 300 nm). In one embodiment, the nanoparticles or nanoshells have a diameter of about 50 to about 250 nm. In another embodiment, the nanoparticles have a diameter of about 150 nm.

In another embodiment, the nanoparticles are coated with PEG.

In yet another embodiment, the nanoparticles are nanoshells. In certain embodiments, the nanoparticles include a silica core and a gold shell.

In certain embodiments, submicron particles make up about 0.5% to about 2% of the pharmaceutical product. In one embodiment, the pharmaceutical product comprises from about 0.5% to about 2% suspension containing nanoparticles. In another embodiment, the pharmaceutical product comprises about 0.1% to about 10% suspension containing nanoparticles.

In one embodiment, the pharmaceutical product contains a surfactant and / or is hydrophilic. In another embodiment, the formulation contains a surfactant and / or is lipophilic. In yet another embodiment, the pharmaceutical product contains a surfactant and / or is in the liposome form. In certain embodiments, the surfactant is less than 10% of the formulation.

In certain embodiments, the pharmaceutical product comprises an ingredient capable of solubilizing lipids. In one embodiment, the component is ethanol.

In one embodiment, the pharmaceutical product comprises one or more of ethanol, isopropyl alcohol, propylene glycol, surfactant, and / or isopropyl adipate. In another embodiment, the formulation comprises hydroxypropyl cellulose (HPC) and carboxymethyl cellulose (CMC). In yet another embodiment, the formulation comprises any one or more of water, ethanol, propylene glycol, polysorbate 80, diisopropyl adipate, phosphoripon, and a thickener.

In certain embodiments, the optical density of the pharmaceutical product is 5 to 500. In one embodiment, the optical density of the pharmaceutical product is about 75. In another embodiment, the optical density of the pharmaceutical product is about 125. In another embodiment, the optical density of the pharmaceutical product is about 250.

In certain embodiments, energy activation, eg, light activation, is achieved using pulsed laser light that supplies light energy at a wavelength absorbed by the particles. In one embodiment, the pulsed laser light provides light energy at a wavelength that is preferentially absorbed by the particles. In another embodiment, energy activation is achieved using a continuous laser that supplies light energy at a wavelength absorbed by the particles.

In one embodiment, the wavelength range of light energy is from about 700 to about 1,100 nm. In another embodiment the fluence of light energy is less than ^{about 100 J / cm 2.} In yet another embodiment, the pulse duration of light energy is from about 0.5 ms to 1,000 ms.

In certain embodiments, the skin is prepared for the method by heating, removing hair follicle contents, and / or by depilation. In one embodiment, the hair follicle contents are removed by a method comprising contacting the hair follicle pores with an adhesive polymer.

In other specific embodiments, topically applied submicron particles are wiped from the skin prior to energy activation. In one embodiment, topically applied submicron particles are wiped from the skin with a fluid prior to irradiation with light radiation. In another embodiment, the fluid is water, ethanol or acetone. In another embodiment, the fluid may be composed of one or more of water, a solvent, a surfactant, and an alcohol.

In other specific embodiments, the skin is heated to a temperature sufficient to aid hair follicle delivery before, during, or after topical application. In one embodiment, heating is achieved by ultrasonic waves. In another embodiment, heating is achieved by steam. In yet another embodiment, heating is achieved by hot packing. In yet another embodiment, heating is achieved with a steamed towel. In general, heating is not sufficient to cause skin pain, tissue damage, burns, or other heat-related effects. In one embodiment, the temperature is about 35-44 ° C. In another embodiment the temperature is about 40-44 ° C. In yet another embodiment, the temperature is about 42 ° C.

In certain embodiments, the exposure step further comprises placing a constant volume of the pharmaceutical product in a container so that the pharmaceutical product is in contact with the skin of interest. In one embodiment, the accelerating step further comprises placing the ultrasonic application device in a container and immersing it in the pharmaceutical product.

In one embodiment, the target volume is the sebaceous glands and the target volume is within the hair follicles beneath the skin.

In another aspect, the invention comprises a plurality of plasmon nanoparticles in an amount effective for inducing thermal denaturation of a cosmetically acceptable carrier and a target tissue site in which the composition is in local contact. A composition comprising particles is provided.

In one embodiment, the plasmon nanoparticles are activated by exposure to energy delivered to the target tissue site from a nonlinear excited surface plasmon resonance source. In another embodiment, the plasmon nanoparticles include a composite material consisting of a metal, a metal composite material, a metal oxide, a metal salt, a conductor, a superconductor, a semiconductor, a dielectric, a quantum dot or a combination thereof. In yet another embodiment, the significant amount of plasmon particles present in the composition comprises geometrically adjusted nanostructures.

In one embodiment, the plasmon particles include nanoplates, solid nanoshells, hollow nanoshells, nanorods, nanorice, nanospheres, nanofibers, nanowires, nanopyramids, nanoprisms, nanostars, or combinations thereof. Includes any currently known or possible geometrical shape that absorbs and produces plasmon resonance at the desired wavelength. In another embodiment, the plasmon particles include silver, gold, nickel, copper, titanium, silicon, galadium, palladium, platinum, or chromium.

In one embodiment, the cosmetically acceptable carrier comprises an additive, a colorant, an emulsifier, a fragrance, a moisturizer, a polymerizable monomer, a stabilizer, a solvent, or a surfactant. In one particular embodiment, the surfactant is from sodium laureth 2-sodium sulphate, sodium dodecyl sulphate, ammonium lauryl sulphate, octtech-1 / deses-1 sodium sulphate, lipids, proteins, peptides or derivatives thereof. It is selected from the group of. In another particular embodiment, the surfactant is present in the composition in an amount of about 0.1 to about 10.0 w / w% of the carrier.

In one embodiment, the solvent is selected from the group consisting of water, propylene glycol, alcohol, hydrocarbons, chloroform, acids, bases, acetone, diethyl ether, dimethyl sulfoxide, dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane, and ethyl acetate. NS.

In another embodiment, the composition has an optical density of at least about 1 O.D. at one or more peak resonance wavelengths. D. Contains plasmon particles that are.

In yet another embodiment, the plasmon particles include a hydrophilic or aliphatic coating, the coating is substantially non-adhering to the skin of the mammalian subject, and the coating is polyethylene glycol, silica, silica-oxide, polyvinylpyrrolidone, polystyrene. , Contains proteins or peptides.

In one embodiment, heat denaturation causes damage, ablation, lysis, degeneration, inactivation, activation, induction of inflammation, activation of heat shock proteins, disruption of cell signaling or disruption of the cellular microenvironment at the target tissue site. include.

In another embodiment, the target tissue site comprises a sebaceous gland, a sebaceous gland component, a sebaceous gland cell, a sebaceous gland cell component, sebum, or a hair follicle infundibulum. In certain embodiments, the target tissue site is hair ridge, hair bulb, stem cell, stem cell niche, dermal papilla, fur, hair epidermis, hair root shear, hair medulla, pyloric muscle, huxley layer, or henle. Includes layers.

In another aspect, the invention is a method of performing targeted ablation of tissue to treat a mammalian subject in need of treatment, i) topical administration of the composition of the invention described above to the skin surface of the subject. And; ii) a step of providing a permeation means for redistributing plasmon particles from the skin surface to the components of the skin tissue; and; ii) a step of irradiating the skin surface with light;

In one embodiment, the light source comprises excitation of mercury, xenone, deuterium, or metal halide, phosphorescence, incandescence, fluorescence, light emitting diodes, or sunlight.

In another embodiment, the permeation means is pretreatment with high frequency ultrasound, low frequency ultrasound, massage, iontophoresis, high pressure airflow, high pressure liquid flow, vacuum, fractionated photothermolysis or dermabrasion. , Or a combination of these.

In yet another embodiment, the irradiation has a light wavelength of about 200 nm to about 10,000 nm, a fluence of about 1 to about 100 joules / cm ² , a pulse width of about 1 femtosecond to about 1 second, and a repetition frequency of about 1 Hz to about 1 THz. Including the light of.

In another aspect, the invention comprises a cosmetically acceptable carrier, an effective amount of sodium dodecyl sulfate, and an amount effective in inducing thermal damage to the target tissue site to which the composition is in local contact. A composition comprising a plurality of plasmon nanoparticles of the above, wherein the nanoparticles have an optical density of at least about 1 O.D. at a resonance wavelength of about 810 nanometers or 1064 nanometers. D. The plasmon particles contain a silica coating of about 5 to about 35 nanometers, and the acceptable carrier provides a composition comprising water and propylene glycol.

In yet another embodiment, the present invention comprises laser ablation of hair or treatment of acne, comprising the composition of the invention described above and a suitable source of plasmon energy to be applied to human skin. Provides a system of.

That is, the present invention relates to the following (1) to (114).
(1) A method for treating or alleviating a target hair follicle skin disease.
a) A step of locally applying a preparation containing submicron particles containing a light absorbing material to the skin of the subject, and
b) Mechanical stirring, acoustic vibration, ultrasound, alternating suction and pressurization, or microjets to facilitate delivery of the material into the skin's hair follicles, sebaceous glands, sebaceous glands, or funnels. And the process to do
c) A step of activating the energy of the submicron particles to treat or alleviate the hair follicular skin disease of the subject.
How to include.
(2) The method according to (1) above, wherein delivery of the material into the hair follicle is facilitated by a microjet generated by ultrasonic waves in the formulation.
(3) The method according to (2) above, wherein the step of activating the energy of the submicron particles comprises irradiating the submicron particles with light and thereby heating the particles.
(4) The method according to (3) above, wherein the submicron particles are in the sebaceous gland during irradiation.
(5) The method according to (4) above, wherein the submicron particles are substantially completely within the sebaceous gland during irradiation.
(6) The method according to (3) above, wherein the submicron particles are in the sebaceous gland duct during irradiation.
(7) The method according to (6) above, wherein the submicron particles are substantially completely in the sebaceous gland duct during irradiation.
(8) The method according to (3) above, wherein the submicron particles are in the funnel portion involved in the hair follicle skin disease.
(9) The method according to (3) above, wherein the light absorbing material in the formulation comprises a photoactive compound, a photodynamic therapy (PDT) prodrug or a PDT drug.
(10) The method according to (3) above, wherein the application of the ultrasonic wave is performed at a frequency in the range of 20 kHz to 500 kHz.
(11) The method according to (3) above, wherein the application of the ultrasonic wave is performed at a frequency in the range of 20 kHz to 100 kHz.
(12) The method according to (3) above, wherein the application of the ultrasonic wave is performed at a frequency in the range of 20 kHz to 60 kHz.
(13) The method according to (3) above, wherein the application of the ultrasonic energy is performed at a frequency in the range of 30 kHz to 50 kHz.
(14) The method according to any one of (10) to (13) above, wherein the ultrasonic output density is about 0.5 to 50 W / cm ^2.
(15) The method according to (14) above, wherein the peak-to-peak amplitude displacement of the ultrasonic horn surface is in the range of 0.5 to 30 microns.
(16) The method according to (3) above, wherein the submicron particle size is selected to pass through the hair follicle and enter the sebaceous glands of the hair follicle.
(17) The method according to (16) above, wherein the hair follicle is a terminal hair follicle.
(18) The method according to (16) above, wherein the hair follicle is a vellus hair follicle.
(19) The method according to (16) above, wherein the hair follicle is a sebaceous hair follicle.
(20) The method according to (3) above, wherein the submicron particle size is about 0.01 micron to about 1.0 micron.
(21) The method according to (3) above, wherein the submicron particle size is about 0.05 micron to about 0.25 micron.
(22) The promotion step further comprises selecting the characteristics of the microjet generated by the ultrasonic wave so that bubbles having substantially the same size as the hair follicle pores are formed in the pharmaceutical product (3). ).
(23) The method according to (22) above, wherein the hair follicle is a terminal hair follicle.
(24) The method according to (22) above, wherein the hair follicle is a vellus hair follicle.
(25) The method according to (22) above, wherein the hair follicle is a sebaceous hair follicle.
(26) The promotion step further comprises selecting the properties of cavitation induced by low frequency ultrasound so that bubbles of approximately the same size as the hair follicles are formed in the formulation (3). ).
(27) The method according to (26) above, wherein the hair follicle is a terminal hair follicle.
(28) The method according to (26) above, wherein the hair follicle is a vellus hair follicle.
(29) The method according to (26) above, wherein the hair follicle is a sebaceous hair follicle.
(30) The method according to (3) above, which is a microjet generated by the ultrasonic wave in the pharmaceutical product within about 50 microns to about 100 microns from the surface of the skin.
(31) The method according to (3) above, wherein the hair follicle disease to be treated is hyperhidrosis, and particles are delivered into the eccrine gland via the eccrine gland duct in the promotion step.
(32) A method for improving the appearance of enlarged pores on the target skin.
a) A step of locally applying a preparation containing submicron particles containing a light absorbing material to the skin of the subject, and
b) Mechanical stirring, acoustic vibration, ultrasound, alternating suction and pressurization, or microjets to facilitate delivery of the material to the skin's hair follicles, sebaceous glands, sebaceous glands, or funnels. And the process to do
c) A step of activating the energy of the submicron particles to improve the appearance of the enlarged pores of the target skin.
How to include.
(33) A method for improving the appearance of the target oily skin.
a) A step of locally applying a preparation containing submicron particles containing a light absorbing material to the skin of the subject, and
b) Delivery of the submicron particles to the skin's hair follicles, sebaceous glands, sebaceous glands, or funnels by alternating mechanical agitation, acoustic vibration, ultrasound, suction and pressurization, or by microjet. And the process of promoting
c) A step of activating the energy of the submicron particles to improve the appearance of the target oily skin.
How to include.
(34) The method according to (3) above, wherein the submicron particles are coated with PEG.
(35) The method according to (10) above, wherein the submicron particles are coated with PEG.
(36) The method according to (16) above, wherein the submicron particles are coated with PEG.
(37) The method according to (35) above, wherein the particles have an absorption peak at a wavelength of light of 700 to 1,100 nm.
(38) The method according to (35) above, wherein the ratio of the shell diameter to the core diameter is about 1.05 to about 2.0.
(39) The method according to any one of (3), (32), (33) or (34) above, wherein the submicron particles are nanoparticles.
(40) The method according to (39) above, wherein the particles are nanoparticles containing a silica core and a gold shell.
(41) The method according to any one of (1) to (40) above, wherein the particles make up about 0.5% to about 2% of the pharmaceutical product.
(42) The method according to (41) above, wherein the preparation is hydrophilic and contains a surfactant.
(43) The method according to (41) above, wherein the preparation is lipophilic and contains a surfactant.
(44) The method according to (41) above, wherein the preparation is a liposome type and contains a surfactant.
(45) The method according to any one of (42), (43) or (44) above, wherein the surfactant is less than 10% of the preparation.
(46) The method according to (41) above, wherein the preparation is hydrophilic.
(47) The method according to (41) above, wherein the preparation is lipophilic.
(48) The method according to (41) above, wherein the composition is a liposome type.
(49) The method according to (39) above, wherein the nanoparticles have a diameter of about 50 to about 250 nm.
(50) The method according to (49) above, wherein the nanoparticles have a diameter of about 150 nm.
(51) The method according to (39) above, wherein the nanoparticles are nanoshells.
(52) The method according to (32) or (33) above, wherein the nanoparticles are coated with PEG.
(53) The method according to any one of (3), (9) or (10) above, wherein energy activation is achieved using pulsed laser light that supplies light energy of a wavelength absorbed by the particles. ..
(54) The method according to (53) above, wherein the wavelength range of the light energy is about 700 to about 1,100 nm.
(55) The method according to (54) above, wherein the fluence of the light energy ^{is less than about 100 J / cm 2.}
(56) The method according to (54) above, wherein the pulse duration of the light energy is about 0.5 ms to 1,000 ms.
(57) The skin is prepared for the method by heating, removing the contents of the hair follicles, and / or by depilation, according to any one of (3), (9) or (10). The method described.
(58) The method of (57) above, wherein the hair follicle contents are removed by a method comprising contacting the hair follicle pores with an adhesive polymer.
(59) The method according to any one of (3), (32) or (33) above, wherein the locally applied submicron particles are wiped from the skin prior to energy activation.
(60) The method according to (59) above, wherein the locally applied submicron particles are wiped from the skin using a fluid before irradiation with light radiation.
(61) The method according to (60) above, wherein the fluid is water, ethanol or acetone.
(62) The method according to (60) above, wherein the fluid may be composed of one or more of water, a solvent, a surfactant, and an alcohol.
(63) The method according to (1) above, wherein the hair follicular skin disease is acne vulgaris or sebaceous hyperplasia.
(64) The method according to (1) above, wherein the irradiation of the submicron particles is performed using a laser.
(65) The skin is heated to about 40-44 ° C. or to a temperature sufficient to aid hair follicle delivery before, during, or after topical application, said (1)-(64). The method described in any of.
(66) The method according to (65) above, wherein the heating is achieved by ultrasonic waves.
(67) The method according to (65) above, wherein the heating is achieved by steam.
(68) The method according to (65) above, wherein the heating is achieved by a hot pack.
(69) The method according to (65) above, wherein the heating is achieved by a steaming towel.
(70) The method of (65) above, wherein the heating is not sufficient to cause the skin pain, tissue damage, burns, or other heat-related effects.
(71) A method for permanently removing the target hair.
a) The step of locally applying the light absorbing material to the target skin and
b) A step of permanently activating the energy of the material and thereby permanently removing the hair.
How to include.
(72) The method according to (71) above, wherein the hair is a light pigmented hair or a fine hair.
(73) The above-mentioned (71), further comprising a step of locally applying the light absorbing material to the skin of the target and removing hair from the hair follicles of the target before performing energy activation of the material. Method.
(74) The method according to (73) above, wherein the material is nanoparticles comprising a silica core and a gold shell.
(75) The method of (73) above, wherein energy activation is achieved using pulsed laser light that supplies light energy at a wavelength that is preferentially absorbed by the particles.
(76) The method of (73) above, wherein energy activation is achieved using continuous laser light that supplies light energy of a wavelength absorbed by the particles.
(77) The method according to (73) above, wherein the skin is prepared for the method by heating, removing the hair follicle contents, and / or hair removal.
(78) A method for treating hyperhidrosis by thermally damaging the eccrine glands or their surrounding areas.
a) The process of locally applying a light-absorbing material to the target skin,
b) A method comprising the steps of energizing the material, thereby permanently removing the glands to treat hyperhidrosis.
(79) A method of facilitating the delivery of a light-absorbing material to a target volume within the skin of a subject to achieve a therapeutic effect.
a) A step of topically applying a pharmaceutical product containing a light-absorbing material to the target skin so that the material is delivered to the reservoir in the skin;
b) A step of promoting delivery of the material to the target volume within the skin of the subject by irradiating the skin with a first series of light pulses.
c) A step of exposing the light absorbing material to a second series of light pulses to heat the material and thermally damaging the target volume to achieve a therapeutic effect.
How to include.
(80) A method of facilitating the delivery of a light-absorbing material to a target volume within the skin of a subject to achieve a therapeutic effect.
a) The step of topically applying the pharmaceutical product containing the light-absorbing material to the target skin, and
b) A step of promoting delivery of the material to the reservoir in the skin by mechanical agitation.
c) Applying a series of low energy laser pulses with a duration of each pulse of 1 microsecond or less facilitates delivery of the material into the target volume within the skin and allows the material to enter the target volume. And the process of making
d) A step of exposing the light absorbing material to a second series of low energy laser pulses to heat the material and thermally damaging the target volume to achieve a therapeutic effect.
How to include.
(81) The method according to any one of (1) to (80) above, wherein the preparation contains a component having an ability to solubilize a lipid.
(82) The method according to (81) above, wherein the component is ethanol.
(83) The method according to any one of (1) to (82) above, wherein the preparation comprises one or more of ethanol, isopropyl alcohol, propylene glycol, a surfactant, and / or isopropyl adipate.
(84) The method according to any one of (1) to (83) above, wherein the preparation comprises hydroxypropyl cellulose (HPC) and carboxymethyl cellulose (CMC).
(85) The above-mentioned (1) to (27), wherein the pharmaceutical product contains any one or more of water, ethanol, propylene glycol, polysorbate 80, diisopropyl adipate, phosphoripone, and a thickener. Method.
(86) The method according to any one of (1) to (85) above, wherein the preparation is a liposome preparation.
(87) The method according to (85) or (86) above, wherein the preparation contains about 0.5 to about 2% of a suspension containing nanoparticles.
(88) The method according to (85) or (86) above, wherein the preparation contains about 0.1 to about 10% of a suspension containing nanoparticles.
(89) A method for treating or alleviating a subject's hair follicle skin disease.
a) A step of locally applying a preparation containing submicron particles containing a light absorbing material to the target skin, and
b) A step of promoting the delivery of the material from the skin into the hair follicle by an acoustically generated microjet in the formulation.
c) The step of activating the energy of the submicron particles to treat the hair follicle skin disease, and the step of treating the hair follicle skin disease.
How to include.
(90) A method for treating or alleviating a target hair follicle skin disease.
a) The step of exposing the skin of the subject to a preparation containing submicron particles containing a light absorbing material, and
b) A step of promoting delivery of the material from the skin into the hair follicle by low frequency ultrasonically induced cavitation in the formulation near the surface of the skin adjacent to the hair follicle.
c) The step of activating the energy of the submicron particles to treat the hair follicle skin disease, and the step of treating the hair follicle skin disease.
How to include.
(91) The method according to (90) above, wherein the exposure step further comprises placing a constant volume of the pharmaceutical product in a container so that the pharmaceutical product comes into contact with the skin of the subject.
(92) The method according to (91), wherein the accelerating step further comprises placing the ultrasonic application device in the container and immersing it in the pharmaceutical product.
(93) A method of facilitating delivery of a light absorbing material to a target volume within the skin of a subject.
a) A step of topically applying a pharmaceutical product containing a light-absorbing material to the target skin so that the material is delivered to a reservoir within the target volume of the skin.
b) Substantially a step of facilitating delivery of the material to the target volume within the skin of the subject by the transhair follicle route.
c) A step of exposing the light absorbing material to a series of light pulses to heat the material and thermally damaging the target volume to achieve a therapeutic effect.
How to include.
(94) The method according to (93) above, wherein the pharmaceutical product has an optical density of 5 to 500.
(95) The method according to (93) above, wherein the pharmaceutical product has an optical density of about 75.
(96) The method according to (93) above, wherein the pharmaceutical product has an optical density of about 125.
(97) The method according to (93) above, wherein the pharmaceutical product has an optical density of 250.
(98) The method according to (93) above, wherein the target volume is a sebaceous hair follicle.
(99) The method of (93), wherein the target volume is in the hair follicle beneath the skin.
(100) The method according to (93) above, wherein the promotion step includes an immersion cavitation step.
(101) The method according to (93) above, wherein the promotion step comprises generating microjets in the formulation.
(102) A method for treating or alleviating a target hair follicle skin disease.
a) A step of locally applying a pharmaceutical product containing particles of a light-absorbing material to the target skin, and
b) A step of causing acoustic cavitation in the pharmaceutical product primarily to selectively facilitate delivery of particles in the pharmaceutical product into the sebaceous glands through the corresponding hair follicles.
c) The step of irradiating the particles with light to treat the hair follicle skin disease, and
How to include.
(103) The method according to (102) above, wherein the particles are formed to a size of about 1 micron to about 5 microns.
(104) The method according to (102) above, wherein the particles are formed in a size that allows the particles to enter or along the hair follicle pores.
(105) The method according to (102) above, wherein the particles have a diameter of about 50 nm to about 250 nm.
(106) The method according to (105) above, wherein the particles are nanoshells.
(107) A method for treating or alleviating a target hair follicle skin disease.
a) A step of locally applying a preparation containing submicron particles containing a light absorbing material to the target skin, and
b) A step of facilitating delivery of the material into the sebaceous glands using immersion cavitation of the formulation.
c) The step of activating the energy of the submicron particles to treat the hair follicle skin disease, and the step of treating the hair follicle skin disease.
How to include.
(108) The method according to (107) above, wherein cavitation occurs within about 50 to 100 microns from the surface of the skin in the promotion step.
(109) A method for treating or alleviating a target hair follicle skin disease.
a) A step of locally applying a preparation containing submicron particles containing a light absorbing material to the target skin, and
b) A step of delivering the formulation substantially into one or more sebaceous glands via the transhair follicle route.
c) The step of activating the energy of the submicron particles to treat the hair follicle skin disease, and the step of treating the hair follicle skin disease.
How to include.
(110) The method of (109) above, wherein the portion of the stratum corneum within the portion of the skin that has undergone the delivery step remains intact.
(111) The method of (109) above, wherein the delivery step is completed using an immersion ultrasonic step and the portion of the stratum corneum that enters the portion of the skin that has undergone the delivery step remains intact. ..
(112) A method for treating or alleviating a target hair follicle skin disease.
a) A step of locally applying a preparation containing submicron particles containing a light absorbing material to the target skin, and
b) A step of promoting delivery of the material into the hair follicle by low frequency ultrasonic induced cavitation near the surface of the skin adjacent to the hair follicle.
c) A step of treating or alleviating the hair follicular skin disease adjacent to the submicron particles by using the heat generated by irradiating the submicron particles with light.
How to include.
(113) The method of (112) above, wherein the induced cavitation occurs from about 50 microns to about 100 microns from the surface of the skin.
(114) The method of (113) above, wherein the characteristics of the low frequency ultrasound are selected such that the stratum corneum is kept intact by cavitation induced near the surface of the skin.
The present invention provides compositions, methods, and systems for treating hair follicular skin diseases. The compositions and articles defined by the present invention are those isolated or otherwise produced in connection with the Examples described below. Other features and advantages of the invention will become apparent from the detailed description and claims.

FIG. 3 is a photomicrograph showing thermal damage to the hair follicle epithelium and sebaceous glands after delivery of the nanoshell suspension by massage. It is a photograph showing the skin surface after applying the nanoshell preparation and promoting the delivery by ultrasonic waves. Before taking this picture, the excess drug was wiped from the skin. It is a micrograph showing a hair follicle filled with dark nanoshells after accelerating delivery by ultrasound. No nanoshells are found in the epidermis or dermis. Micrographs showing hair follicles and surrounding skin after ultrasound delivery and laser irradiation of nanoshells, visualized with hematoxylin and eosin (H & E staining). Selective thermal damage around the hair follicle is shown by adding a black line. It is a photograph showing the skin surface. Accumulation of nanoshells is seen in the hair follicles. It is a micrograph showing the hair follicle in which nanoshells are remarkably accumulated. FIG. 3 is a photomicrograph showing local thermal damage to hair follicles containing sebaceous glands, visualized using H & E staining. It is a table showing the effectiveness of laser treatment of back acne in human clinical trials after nanoshell delivery.

The present invention features compositions containing light / energy absorbing materials and methods useful for their topical delivery to targets (eg, hair follicles, hair follicle infundibulum, sebaceous glands) for treating hair follicle disorders. And.

Definitions Unless defined otherwise, all scientific and technological terms used herein have the meaning generally understood by one of ordinary skill in the art to which the invention belongs. The following references provide those skilled in the art with many general definitions of the terms used in the present invention: Singleton et al. , Dictionary of Microbiology and Molecular Biology (2nd Edition 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); , R. Rieger et al. (Eds.), Springer Verlag (1991); and Hale & Maham, The HarperCollins Dictionary of Biology (1991). As used herein, the following terms have meanings based on them below, unless otherwise noted.

By "alleviating" is meant reducing, suppressing, attenuating, reducing, blocking, or stabilizing the onset or progression of a skin disease or symptom. One of the exemplary skin symptoms is acne vulgaris.

The terms "compound" and "material" are used interchangeably and refer to the active ingredient according to the invention.

In the present disclosure, "comprises," "comprising," "contining," "having," and the like may have meanings based on them in US patent law. It can mean "includes", "includes", etc .; "consisting essentially of" or "consentially", etc. are in US patent law. It has a base meaning, the term is open-ended, and can exist other than what is described, as long as it is not changed by something other than the one that describes the basic or new characteristics of what is described. However, embodiments of the prior art are excluded.

"Detecting" refers to confirming the presence or absence or amount of a test substance (analyte) to be detected.

"Effective amount" means the amount required to reduce the symptoms of the disease compared to an untreated patient. The effective amount of the active compound used in the practice of the present invention for the therapeutic treatment of the disease will vary depending on the method of administration, age, body weight and general health of the subject. Ultimately, your doctor or veterinarian will determine the appropriate dosage and dosage. Such quantities are referred to as "effective" quantities.

"Energy activation" means stimulation by an energy source that causes thermal or chemical activity. Energy activation may be performed by any energy source known in the art. Exemplary energy sources include lasers, ultrasonic waves, sound sources, flash lamps, ultraviolet light, electromagnetic wave sources, microwaves, or infrared light. Energy absorbing materials absorb energy and become thermally or chemically active.

The terms "light", "light energy", "optical energy" and "light emission" are used interchangeably herein.

As used herein, "obtaining" as in "obtaining a drug" includes synthesizing, purchasing, or otherwise acquiring the drug.

The phrase "pharmaceutically acceptable carrier", as used herein, carries the energy-activating material of the invention into or into a subject so that it can perform its intended function. Or means a pharmaceutically acceptable material, composition or solvent such as a liquid or solid filler, diluent, excipient, solvent or capsule substrate required for transport. Each carrier must be "acceptable" in the sense that it is compatible with the other components of the formulation and is not harmful to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose, and fructose; starches such as corn starch and potato starch; cellulose, and sodium carboxymethyl cellulose, ethyl cellulose. And cellulose derivatives such as cellulose acetate; tragacanto powder; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, benivana oil, sesame oil, olive oil, corn oil and soybean oil; Glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; no exothermic substances Water; isotonic physiological saline; Ringer's solution; ethyl alcohol; phosphate buffer; as well as other non-toxic compatible substances used in pharmaceutical formulations. Preferred carriers include surface action and solvent transport such that the energy activating material is carried into or around the pores, eg, into the sebaceous glands, into the keratotic plug, into the funnel and / or into the sebaceous glands and funnel. Some can enter the pores.

By "reducing" is meant a negative change of at least 10%, 25%, 50%, 75%, or 100%.

"Criteria" means a standard or control state.

"Subject" means a mammal, including, but not limited to, humans or non-human mammals such as cows, horses, dogs, sheep, or cats.

The scope described herein is understood to be an abbreviation for all values that fall within that scope. For example, the range of 1 to 50 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21. , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46. , 47, 48, 49, or any number selected from the group consisting of 50, combinations of numbers, or subranges.

As used herein, terms such as "treat," "treating," and "treatment" refer to reducing or alleviating the disorder and / or associated symptoms. Point to. It will be found that treatment of a disorder or symptom does not require the complete elimination of the disorder, symptom or its associated symptoms, but does not rule out it.

Unless otherwise noted or contextually apparent, the term "or" as used herein is understood to be inclusive. Unless otherwise noted or contextually apparent, the terms "one (a)", "one (an)", and "the" as used herein are singular or plural. Is understood to be.

Unless otherwise noted or contextually apparent, the term "about" as used herein is understood to be within normal tolerances in the art, eg, within 2σ (σ = standard deviation) of the mean. Will be done. About 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05 of the stated values. It can be understood that it is within% or 0.01%. Unless the context makes clear, all numbers described herein are modified by the term about.

The listing of chemical groups in any definition of variables herein includes the definition of variables as any single group or a combination of listed groups. The description of one embodiment with respect to variables or embodiments herein includes embodiments as any single embodiment or in combination with any other embodiment or a portion thereof.

Any composition or method described herein can be combined with any one or more of the other compositions and methods described herein.

Mechanism of onset of hair follicle disease The sebaceous gland is a component of the hair follicle sebaceous system. They are present throughout the body, especially on the face and upper trunk, and produce sebum, a lipid-rich secretion that coats the surface of hair and epidermis. The sebaceous glands are involved in the pathogenic mechanism of several diseases, the most frequent of which is acne vulgaris. Acne is characterized by obstruction of hair follicles by keratinocytes formed by abnormal detachment of keratinocytes in the funnel (upper part of the hair follicle) in a situation where excess sebum is produced by the hyperactive sebaceous glands. It is a multifactorial disease.

The funnel is an important site for the pathogenic mechanism of many hair follicular diseases (eg, acne). There is evidence that abnormal proliferation and desquamation of keratinocytes in the funnel results in the formation of microacne, followed by clinically visible hair follicle "keratinocytes" or acne. Since the structure of the funnel is important for the pathogenesis of acne, this part of the hair follicle is selectively destroyed by energy targeting assisted by energy-activating materials, such as laser targeting, to destroy the lesion site. Eliminate or reduce.

Topical Delivery of Light / Energy Absorbing Material The present invention provides delivery of light / energy absorbing material into the skin appendages of hair follicles, particularly into the hair follicle infundibulum and sebaceous glands, by topical application. In one embodiment, such materials are useful in the treatment of hair follicular diseases such as acne (eg, acne vulgaris), hyperhidrosis. After introducing an energy-activating material into the sebaceous glands, exposure to energy (light) with a wavelength corresponding to the absorption peak of the chromophore increases local light absorption of the tissue and selectively heat damage to the sebaceous glands. Occur.

In another embodiment, the skin of the subject is coated with a light absorbing material to facilitate delivery into the eccrine gland via the eccrine duct and energy activation of the material to result in the eccrine glands or their surrounding areas. There is a treatment for hyperhidrosis by heat-damaging. The method thereby permanently removes the eccrine glands. In one aspect, the method of treating hair follicle disease is a method of treating hyperhidrosis.

Skin Preparation If necessary, prepare the skin by one or a combination of the following methods. Delivery of the light-absorbing material can be facilitated by removing the hair, which is done prior to topical application of the light-absorbing material. Optionally, degreasing the skin before applying the light absorbing compound. Before applying sebashells, for example, an acetone wipe is used to degreas the skin, especially to remove sebum and hair follicle contents.

For certain subjects, delivery can be facilitated by reducing or removing the clogging of hair follicles prior to application of the light absorbing material. By removing the blockage in this way, the delivery of the nanoshell can be improved. Hair follicles, especially those of patients who are prone to acne, are clogged with exfoliated keratinocytes, sebum, and the bacterium P. Acnes. Hair follicles can be emptied by vacuuming. Other methods include strips with components such as cyanoacrylate exfoliation, polyoctanium 37 (eg, Biore pore removal strips). The polymer flows into the hair follicles and dries over time. When the dried polymer film is peeled off, the contents of the hair follicle are pulled out and the hair follicle is emptied.

Optionally, the skin can be heated before applying the light absorbing material. By heating, the viscosity of sebum decreases, and the components of sebum can be liquefied. This can facilitate delivery of the light absorbing material (eg, formulated as a nanoshell) to the hair follicles.

Topical delivery of light-absorbing material A light-absorbing material, such as a non-toxic dye (eg, indocyanine green or methylene blue), is applied topically to the skin after the desired preparation. The top-applied preparation containing the light-absorbing material may contain ethanol, propylene glycol, a surfactant, and acetone. Such additional ingredients facilitate delivery into the hair follicle.

Delivery of the light absorbing material is facilitated by the application of massage, acoustic vibrations in the range of 10 Hz to 20 kHz, ultrasonic waves, alternating suction and pressurization, and mechanical agitation such as jets. In one embodiment, the light absorbing material is delivered as nanoparticles such as nanoshells or nanorods that absorb light in the visible and near infrared regions of the electromagnetic spectrum. In another embodiment, the light absorbing material is a quantum dot. Preferably, the light absorbing material is formulated for topical delivery in a form that facilitates hair follicle delivery. In one embodiment, such formulations include water, ethanol, isopropyl alcohol, propylene glycol, surfactants, and isopropyl adipate and related compounds. In one embodiment, the pharmaceutical product is hydrophilic and contains a surfactant. In another embodiment, the formulation is lipophilic and contains a surfactant. In yet another embodiment, the composition is liposomal and contains a surfactant. In any of the above embodiments, the surfactant is less than 10% of the pharmaceutical product. In another embodiment, the formulation is hydrophilic. In yet another embodiment, the formulation is lipophilic. In yet another embodiment, the composition is liposomal.

Ultrasound Accelerated Delivery Ultrasound was used to achieve transdermal delivery of the compound into the body. Ultrasound produces shock waves and microjets due to bubble cavitation, which appear to form channels in the skin and transport the molecule of interest. Previously, efforts have been made to deliver the compound through the stratum corneum. Small molecules, eg, small molecules less than 5 nm in size, can be delivered through the stratum corneum. As the particle size increases, the rate of delivery through the stratum corneum decreases significantly. For example, for particles with a size of 50 nm or more, the delivery rate through the stratum corneum is very low. However, this size is much smaller than the pore openings and hair follicle funnels. For example, the use of a 150 nm sized silica core and gold shell structure, much smaller than the funnel diameter, has been shown to result in less deposition in the skin through the stratum corneum.

Based on these findings, the infundibulo-sebaceous unit is selectively heat-damaged by pulsed laser irradiation after first delivering an appropriately sized light-absorbing material. It provides the basis for targeting acne treatment. Here, ultrasound facilitates delivery of the light absorbing material, in particular, into the hair follicle structure. Shock waves, microjet generation, and streaming deliver light-absorbing particles into the hair follicle funnel and associated sebaceous ducts and sebaceous glands.

Ultrasound often involves heating the skin, which is the target organ. Heating, eg, heating below about 42 ° C., can aid in hair follicle delivery. However, overheating is not desirable as it causes pain, tissue damage, and burns. In one embodiment, overheating can be avoided, for example by cooling the skin. In another embodiment, the topically applied formulation or coupling gel may be pre-cooled or parallel cooled. Also, low duty ratios and repetitive ultrasonic pulse bursts can be used to avoid overheating, in which case the body cools the skin receiving ultrasonic energy during off hours.

In certain embodiments, the present invention provides two ultrasonic delivery methods. One is "contact ultrasound" and the other is "immersion ultrasound".

According to one embodiment of the contact ultrasonic method, the formulation of the present invention is applied topically to the skin by spreading it on a thin layer, and a horn vibrating at an ultrasonic frequency is brought into contact with the skin coated with the formulation.

According to one embodiment of the immersion ultrasound method, a reservoir filled with the formulation is placed on the skin and the horns are spaced in the horns in the range of about 2 mm to about 30 mm so that the horns do not come into contact with the skin. After soaking, the horn is vibrated at the ultrasonic frequency.

Acoustic cavitation is often the effect observed by ultrasound in a liquid. In acoustic cavitation, sound waves apply a sinusoidal pressure to the cavities present in a solution. During the negative pressure cycle, the liquid is pulled away at the "weak point". Such weaknesses may be existing bubbles or solid nucleation sites. In one embodiment, a bubble is formed, which grows to a critical size known as its resonant size (Leong et al., Acoustics Australia, 2011-acoustics. Asn.au, THE FUNDAMENTALS OF POWER ULTRASOUND-A. REVIEW, p54-63). According to Mitragotri (Biophyss J. 2003; 85 (6): 3502-3512), spherical collapse of bubbles results in a high pressure core that produces a shock wave with an amplitude greater than 10 kbar (Pecha and Gompf, Phys. Rev. Lett. 2000; 84: 1328-1330). In addition, the aspherical collapse of bubbles near the boundary of the skin or the like produces a microjet having a velocity of about 100 m / s (Popinet and Zaleski, 2002; J. Fluid. Tech. 464: 137-163). Such bubble collapse phenomena can aid in the delivery of materials into skin appendages such as hair and sebaceous hair follicles. Thus, in various embodiments of the invention, to optimize pre-collapse bubble size to facilitate efficient delivery of the light absorbing material into the intended target (eg, sebaceous glands, hair follicles). , Immersion ultrasonic method is provided.

The resonant size of the bubble depends on the frequency used to generate the bubble. A simple schematic relationship between resonance and bubble diameter is F (unit: Hz) x D (unit: m) = 6 m. It is given in Hz (in the equation, F is a frequency expressed in Hz and D is a bubble diameter (size) expressed in m). In practice, the bubble diameter is usually smaller than the bubble diameter predicted by this equation because the bubble pulsation is non-linear.

Table 1 below describes the size of the resonant size of the bubble as a function of frequency, calculated from the above relationship.

Computer simulation of bubble vibration provides a more accurate estimate of bubble size. For example, a study by Yasui (J. Acost. Soc. Am. 2002; 112: 1405-1413) investigated depths at three frequencies. The size of single bubble sonoluminescence (SBSL) stable cells is relatively small and the range is shown in Table 2 below (estimated from FIGS. 1, 2, and 3 of Yasui, 2002).

There is an optimal cavitation bubble size range for efficient delivery into the hair follicle using cavitation bubbles. A strong cavitation shock wave generated by relatively large bubbles is required. However, if the bubble size is too large, a strong shock wave may be generated, which may compress the skin, reducing the pore size and reducing efficient delivery to the target (eg, sebaceous glands, hair follicles). For example, if the bubble size is much larger than the hair follicle opening, the resulting shock wave will compress not only the pore opening but also the skin around the pore opening. This hinders efficient delivery into the hair follicle opening. Desirably, the bubble size should be approximately the same size as the target pores. The typical hair follicle pore size of human skin is estimated to be in the range of 12-300 microns. Therefore, the advantageous ultrasonic frequency range is 20 kHz to 500 kHz. In another alternative, the application of ultrasonic frequencies is in the range of 20 kHz to 100 kHz, or 20 kHz to 60 kHz, or even 30 kHz to 50 kHz. The desired power density is estimated to be in the range of ^{0.5-50 W / cm 2.} This is sufficient to generate cavitation bubbles in the desired size range.

"Immersion cavitation", as used herein, is defined as the formation and disintegration of cavitation bubbles by ultrasonic energy in a fluid formulation.

In view of the above description, delivery of the light-absorbing material into the hair follicle is performed by selecting the characteristics of the microjet that acoustically generates bubbles so that bubbles of approximately the same size as the hair follicle pores are formed in the pharmaceutical product. It also provides a way to promote it. Depending on the properties selected, the bubbles can be approximately the same size as terminal hair follicles, vellus hair follicles, or sebaceous hair follicles. In another alternative implementation in view of the above description, by selecting the properties of low frequency ultrasound-induced cavitation so that bubbles of approximately the same size as the hair follicle are formed in the formulation, within the hair follicle. Also provided is a method of facilitating the delivery of the light absorbing material to. In one practice, the hair follicles are terminal hair follicles. In another practice, the hair follicles are vellus hair follicles. In yet another practice, the hair follicles are sebaceous hair follicles. In yet another embodiment, ultrasonically generated microjets or low frequency ultrasonically induced cavitation occurs in the formulation from about 50 microns to about 100 microns from the surface of the skin.

In another embodiment, a method for treating or alleviating a hair follicular skin disease of a subject is also provided. The method comprises exposing the subject's skin to a formulation comprising submicron particles comprising a light-absorbing material to the subject's skin. Next, there is a step of promoting the delivery of the material from the skin into the hair follicle by cavitation induced by low frequency ultrasonic waves in the formulation near the surface of the skin adjacent to the hair follicle. The submicron particles are then energized to treat hair follicular skin disease. In one alternative, there is also the step of exposing the pharmaceutical product by placing it in a container in a certain volume so that the pharmaceutical product comes into contact with the skin of the subject. Furthermore, there is also a step of accelerating the method by placing an ultrasonic application device in a container and immersing it in a pharmaceutical product.

Yet another embodiment provides a method of facilitating delivery of a light absorbing material to a target volume within the subject's skin. The method comprises the step of topically applying a formulation containing a light absorbing material to the skin of the subject so that the material is delivered to a reservoir within the target volume of the skin. Next, there is a step of facilitating delivery of the material to a target volume within the subject's skin substantially by the transhair follicle route. Next, there is a step of exposing the light absorbing material to a series of light pulses to heat the material and thermally damage the target volume to achieve a therapeutic effect. In one alternative, the optical density of the pharmaceutical product is 5 to 500. In another alternative, the optical density of the pharmaceutical product is about 75. In yet another alternative, the optical density of the pharmaceutical product is about 125. In yet another alternative, the optical density of the pharmaceutical product is about 250. In one aspect, the target volume is the sebaceous gland. In another aspect, the target volume is within the hair follicles beneath the skin.

In yet another embodiment, the accelerating step comprises an immersion cavitation step. Another alternative is to provide a step of facilitating delivery into the sebaceous glands using immersion ultrasound. In one alternative, the facilitation step involves generating microjets in the formulation. In one aspect, the step of accelerating using ultrasound causes cavitation at about 50-100 microns from the surface of the skin in the formulation. In any of the above-mentioned methods, there is also a step of causing acoustic cavitation in the pharmaceutical product in order to selectively promote the delivery of the particles in the pharmaceutical product into the sebaceous glands mainly through the corresponding hair follicles. After that, there is a step of irradiating the particles with light to treat a hair follicle skin disease. In one embodiment, the particles are formed to a size of about 1 micron to about 5 microns. In another aspect, the particles are sized to fit into or along the hair follicle pores. In yet another embodiment, the particles are about 50 nm to about 250 nm in diameter. In another embodiment, the particles are nanoshells.

Energy (light) activation After topical application and accelerated delivery (eg, by mechanical agitation, ultrasound), wipe over the skin to remove residual light-absorbing material. After this, energy (light) irradiation is performed. Light is absorbed by the material inside the hair follicles or sebaceous glands, causing local heating. The light source depends on the absorber used. For example, in a nanoshell having a wide absorption spectrum adjusted to a resonance wavelength of 800 nm, a light source such as 800 nm, 755 nm, 1,064 nm or high intensity pulsed light (IPL) with appropriate filtering can be used. In one aspect, the nanoparticles in the suspension have an absorption peak at a wavelength of 700-1,100 nm. Such pulsed laser irradiation causes thermal damage to the tissue surrounding the material. In one aspect, the fluence of light energy is less than about 100 J / cm2. Damage to hair follicle stem cells and / or sebaceous glands in the funnel improves hair follicle symptoms such as acne. Such a method can be used not only for particulate matter in suspension but also for small molecules dissolved in solution. These can include pharmaceuticals, photodynamic therapy (PDT) prodrugs, or PDT drugs.

Suitable energy sources include light emitting diodes, incandescent lamps, xenon arc lamps, lasers or sunlight. Preferable examples of continuous wave devices include, for example, diodes. Suitable flash lamps include, for example, pulsed dye lasers and alexandrite lasers. Short pulse red dye lasers (504 and 510 nm) are typical lasers with wavelengths that are strongly absorbed by chromophores, such as laser sensitive dyes, in the epidermis and funnel but not in the sebaceous glands. A copper steam laser (511 nm) and a Q-switch Neodim (Nd) with a wavelength of 1064 nm that can double the frequency using potassium diphosphate crystals to generate visible green light with a wavelength of 532 nm: YAG laser. Will be. The process employs selective photoactivation that matches the wavelength of an energy (light) source, eg, a laser, to the absorption spectrum of a selected energy-activating material, preferably a chromophoreic agent. ..

Higher light-absorbing material concentrations are more likely to be achieved in the funnel than in the sebaceous tubes and sebaceous glands, which have relatively high resistance to material transport. In principle, hair follicles containing sebaceous glands can be irreversibly damaged only by light absorption other than the material inside the funnel. This is caused by damage to the keratinocytes in the hair follicle epithelium. Also, relatively high energy pulses can be used to magnify thermal damage to include stem cells, hair ridges, and the perimeter of the sebaceous glands within the outer root sheath. However, such high energies should not cause unwanted side effects. Such side effects can be mitigated by using epidermal cooling and a relatively long pulse duration ranging from about a few milliseconds to 1,000 ms.

Acne can be ameliorated by thermal changes in the funnel itself and slight improvements in the sebaceous glands. The appearance of enlarged facial pores is a common problem for many. This is typically due to the enlargement of the sebaceous glands, the enlargement of the funnel, and the enlargement of the pore openings. The heat of the tissue, especially collagen, causes the tissue to shrink. Delivery of the nanoshell, as well as its thermal targeting within the funnel gland system, including the upper funnel, lower funnel, and sebaceous glands, will improve the appearance of enlarged pores.

Energy Absorbent Material Formulation The present invention provides a composition comprising a light / energy absorption material for topical delivery. In one embodiment, the particles in the composition are nanoparticles comprising a silica core and a gold shell. In yet another embodiment, the compound of the invention comprises a silica core and a gold shell (150 nm). In another embodiment, the nanoshell used is composed of a silica core having a diameter of 120 nm and a gold shell having a thickness of 15 nm, and has a total diameter of 150 nm. The nanoshell is coated with a MW 5,000 PEG layer. The PEG layer prevents and / or reduces nanoshell aggregation, thereby improving the stability of the nanoshell suspension and extending shelf life. In one embodiment, the nanoparticles have a diameter of about 50 to about 250 nm. In some embodiments, the ratio of shell diameter to core diameter of the particles used herein is from about 1.5 to about 2.0. In another aspect, the particles in the formulation make up about 0.5% to about 2% of the formulation.

The nanoparticles of the present invention exhibit surface plasmon resonance, which causes incident light to induce optical resonance of surface plasmons (vibrations of electrons) in the metal. The peak absorption wavelength can be "tuned" to the near-infrared (IR) portion of the electromagnetic spectrum. Due to their submicron size, these nanoparticles can enter the funnel, sebaceous ducts and sebaceous glands of the epidermis, minimizing penetration into the stratum corneum. In certain embodiments, selective transhair follicle penetration of nanoparticles with a diameter of about 150-350 nm is achieved. In one aspect, a method of treating or alleviating a subject's hair follicular skin disease is provided. There is a step of topically applying a preparation containing submicron particles containing a light absorbing material to the target skin. Next, there is a step of delivering the pharmaceutical product into one or more sebaceous glands substantially by the transhair follicle route. Next, there is a step of activating the energy of the submicron particles to treat the hair follicle skin disease. In one aspect, the portion of the stratum corneum within the portion of the skin that has undergone the delivery step remains intact. Furthermore, the delivery step is completed using the immersion ultrasonic step, and the portion of the stratum corneum within the portion of the skin that has undergone the delivery step remains intact.

If desired, the light / energy absorbing material is provided mixed with a solvent formulated for topical delivery. In one embodiment, the compositions of the invention include, but are limited to, one or more of surfactants such as ethanol, isopropyl alcohol, propylene glycol, polysorbate 80, phosphoripon 90, polyethylene glycol 400, and isopropyl adipate. Drugs that improve hair follicle delivery are formulated. In another embodiment, the composition of the present invention comprises, but is not limited to, hydroxypropyl cellulose (HPC) and carboxymethyl cellulose (CMC) in order to improve the handleability of the pharmaceutical product. A thickener is added.

Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, mold release agents, coating agents, sweeteners, flavoring agents and fragrances, preservatives and antioxidants are also compositions. May be present in.

Liquid dosage forms for topical administration of the compositions of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, creams, lotions, ointments, suspending agents, and syrups. Be done. In addition to the active ingredient, liquid dosage forms include inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate. , Ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, peach oil, almond oil and sesame oil), It may contain glycerin, tetrahydrofuryl alcohols, fatty acid esters of polyethylene glycol and sorbitan, and mixtures thereof.

In addition to active compounds, suspending agents include, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof. It may contain a turbidizing agent.

In addition to the active compounds of the present invention, ointments, pastes, creams and gels include animal and vegetable fats, oils, waxes, paraffins, starches, tragacants, cellulose derivatives, polyethylene glycols, silicones, bentonites and kei. Excipients such as acids, talc and zinc oxide or mixtures thereof may be included. The term "cream" is recognized in the art and is intended to include semi-solid emulsions containing both oil and water. The oil-in-water cream is a water-soluble cream (Aqueous Cream) BP that is miscible and is sufficiently absorbed by the skin. Water-in-oil (oil-based) creams are immiscible with water and are therefore relatively difficult to remove from the skin. These creams are emollients that smooth and moisturize the skin, eg, Oily Cream BP. Both of these systems require the addition of natural or synthetic surfactants or emulsifiers.

The term "ointment" is recognized in the art and includes systems having oils or fats as its continuous phase. The ointment is a semi-solid anhydrous substance that has occlusive, emollient, and protective effects. Ointments limit transdermal water loss and therefore have hydration and moisturizing effects. Ointments can be broadly classified into two groups: oily, for example, white soft paraffin (petroleum, petrolatum) and water-soluble, for example, macrogol (polyethylene glycol) ointment (Ointment) BP. The term "lotion" shall include solutions commonly used in dermatology that are recognized in the art. The term "gelling agent" is recognized in the art and is intended to include high molecular weight polymers such as carboxypolymethylene (Carbomer BP) or semi-solid permutations gelled with methyl cellulose. It can be regarded as a semi-plastic aqueous lotion. They are usually non-greasy, water-miscible, easy to apply and wash off, and are particularly suitable for the treatment of hairy areas of the body.

Subject Monitoring During treatment using the compositions or methods of the invention, the condition or treatment of the subject's disease with a skin disorder or disorder can be monitored. Such monitoring can be useful, for example, in assessing the effectiveness of a particular drug or treatment regimen in a patient. Therapies that promote skin health or improve the appearance of the skin are considered to be particularly useful in the present invention.

Kit The present invention provides a kit for treating or preventing a skin disease or disorder, or a symptom thereof. In one embodiment, the kit comprises a pharmaceutical pack containing an effective amount of light / energy absorbing material (eg, a nanoshell with a silica core and a gold shell (150 nm)). Preferably, the composition is present in unit dosage form. In some embodiments, the kit comprises a sterile container containing a therapeutic or prophylactic composition, such container being a box, ampoule, bottle, vial, tube, bag, pouch, blister pack, or such container. It may be another suitable container form known in the art. Such containers may be made of plastic, glass, laminated paper, metal foil, or other material suitable for holding pharmaceuticals.

If desired, the compositions of the invention or combinations thereof are provided with instructions for administering them to subjects with or at risk of developing a skin disease or disorder. Instructions for use generally include information regarding the use of the composition to treat or prevent a skin disorder or disorder. In other embodiments, the instructions for use describe the following, ie, compounds or combinations of compounds; skin symptoms associated with acne, dermatitis, psoriasis, or any other characteristic of inflammation or bacterial infection. Dosage schedule and administration to treat skin symptoms or their symptoms; Precautions; Warnings; Infections; Contraindications; Overdose information; Side effects; Animal pharmacology; Clinical trials; and / or at least one of the references. include. Instructions for use may be printed directly on the container (if any), affixed to the container as a label, or provided in or with the container as a separate sheet, pamphlet, card, or folder. good.

The listing of chemical groups in any definition of variables herein includes the definition of variables as any single group or a combination of listed groups. The description of an embodiment with respect to variables or embodiments herein includes embodiments as any single embodiment or in combination with any other embodiment or a portion thereof.

The following examples are provided to illustrate the invention and are not intended to limit the invention. Those skilled in the art will appreciate that various modifications consistent with the invention described above can be made to the particular configurations described below, while retaining the important properties of the compounds or combinations thereof.

Laser Hair Removal The present invention features compositions and methods useful for laser hair removal, especially laser hair removal of light-colored hair. Laser hair removal uses light of a specific wavelength and pulse duration to ensure optimal action on the targeted tissue while minimizing action on the surrounding tissue. The laser selectively heats the dark target, melanin, but does not heat the rest of the skin, which can cause local damage to the hair follicles. Because lasers target melanin, light-colored hair, gray hair, and fine or fine hair with low melanin levels are not effectively targeted by existing laser hair removal methods. Efforts have been made to deliver various light absorbing materials such as carbon particles, extracts from squid ink commercially known as meladine, or pigments into hair follicles. These methods are largely ineffective.

The present invention provides fine particles in the form of a suspension that is topically applied after preparing the skin as described above. In particular, it prepares the skin by removing the hair shaft and delivers the light-absorbing material to the hair follicles. Preferably, the formulation is optimized for hair follicle delivery with mechanical agitation for a specific time period. After wiping the pharmaceutical product from the top of the skin, laser irradiation is preferably performed while cooling the surface. The laser is pulsed out with a pulse duration of about 0.5 ms to 400 ms, or 0.5 ms to 1,000 ms, using wavelengths absorbed by the particles or nanoshells. This method permanently removes unpigmented or thinly pigmented hair by destroying stem cells and other hair-growth organs at the hair follicles and hair bulb sites.

Unless otherwise specified, the practice of the present invention employs conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are well within the scope of those skilled in the art. There is. Such techniques include "Polymer Cloning: A Laboratory Manual", second edition (Sambrook, 1989); "oligonucleotide Cloning" (Gait, 1984); "Animal Cell Handbook of Experimental Immunology ”(Weir, 1996);“ Gene Transfer Vectors for Mullisan Cells ”(Miller and Callos, 1987);“ Current Protocol 1987 ”; Mullis, 1994); well described in literature such as "Cellent Protocols in Immunology" (Polygan, 1991). These techniques are applicable to the production of polynucleotides and polypeptides of the invention and can be considered as such in the production and practice of the invention. Techniques that are particularly useful for a particular embodiment are discussed in the following sections.

The following examples are described to provide those skilled in the art with complete disclosure and description of how the assay, screening, and therapeutic methods of the invention are performed and used. Does not limit the scope of what the inventors consider to be the invention.

Example 1: Local delivery of nanoshells to the hair follicle epithelium for treating hair follicle disease Examples will be described using massage as a mechanical means of hair follicle delivery. A nanoshell suspension adjusted to 800 nm was massaged and rubbed into the depilated pig skin of live pigs in vivo. After wiping the suspension on the skin, laser energy was applied with parallel contact cooling. A biopsy was performed and a routine histological examination was performed. A micrograph of the tissue structure is shown in FIG. Thermal damage to the hair follicle epithelium and part of the sebaceous glands is observed. Such injuries are useful in the treatment of hair follicular disorders such as acne or in improving the appearance of the subject's oily skin.

One of the exemplary methods of treatment described above comprises the step of topically applying a formulation containing submicron particles containing a light absorbing material to the skin of the subject. The material is then delivered to the hair follicles, sebaceous glands, sebaceous ducts, or funnels of the skin by alternating mechanical agitation, acoustic vibration, ultrasound, suction and pressurization, or by microjets. There is a process to do. After that, there is a step of activating the energy of the submicron particles to treat the hair follicle skin disease.

Example 2: Local delivery of nanoshells to the hair follicle epithelium for laser hair removal In preparation for laser hair removal, the flank of the pig was depilated by waxing. The skin was then heated and evacuated to empty the skin's hair follicle contents. It was then delivered by massaging and rubbing fine particles of a silica core: gold shell coated with PEG and having an approximate size of 0.150 micrometer in diameter. The skin was wiped to remove material from above the skin. After that, pulsed laser irradiation was performed at 800 nm. Samples were removed, fixed in formalin and treated by routine histological examination (H & E staining). Thermal damage to the hair follicle structure was noted by histological examination.

Example 3: Light Pulse Induced Pressure Pulse Accelerated Delivery A pharmaceutical product containing a light absorbing material is applied onto the skin. This can be done by methods known in the art, including but not limited to mechanical assists such as passive diffusion, heating, pressure pulsing, vibration, acoustic coils, ultrasound, nozzles, or combinations described above. Move into the funnel of the funnel sebaceous system. A pulse of light is then applied using a handpiece with a built-in cooling plate that can be pressed against the skin. When the material is heated with a first light pulse, expansion occurs with or without the formation of vapor bubbles. As a result, a pressure pulse is generated. During the pressure pulse, pressure is applied to the skin with a cooling plate. Since pressure cannot escape from the skin, the material passes through low resistance channels in the skin, such as the sebaceous gland duct, to reach the sebaceous glands. For example, the pulse duration of this pulse is usually short, eg, 1 ns to 1 ms, preferably 10 ns to 100 microseconds, so that the magnitude of the pressure pulse due to vapor bubble formation is maximized. Once the material enters the target sebaceous gland, it irradiates light with a pulse duration and radiation exposure appropriate for the size of the target sebaceous gland. The light-absorbing material is heated, causing thermal damage to the sebaceous glands, thus inactivating the sebaceous glands and ameliorating acne vulgaris, as well as other hair follicular diseases and symptoms associated with the presence or activity of the sebaceous glands.

In a related method, a series of low energy laser pulses with a pulse duration of 1 microsecond or less is used, preferably in the acoustic range of pulse repetition frequencies, to activate the particles. This activation causes the particles to be violently "stirred", some of which enter the sebaceous glands through the funnel.

Example 4: Use of ultrasound to deliver light-absorbing material to hair follicles and sebaceous glands The skin of pig ears was cryopreserved. Before the experiment, it was thawed. Wax was applied to remove the hair and a piece of pig's ear was placed on the bottom of the cup with the skin facing up. It was filled with a 150 nm diameter silica core / gold shell nanoshell formulation (Sebacia, Inc., Duluth, GA) at an optical density of about 250. A 20 kHz acoustic engineering device horn was immersed in the formulation so that the distance between the distal surfaces of the horn at the top of the skin was about 5 mm. The diameter of the horn was 13 mm and the output was about 6 W. Therefore, the output density during the on-time was 4.5 W / cm2. The device was turned on with a duty ratio of 50% and on and off times per cycle of 5s and 5s, respectively. It was applied for 4 cycles. After wiping the skin to remove excess pharmaceuticals, the skin was irradiated with a laser beam having a wavelength of 800 m with a spot of 9 mm × 9 mm, a total radiation exposure of about 50 J / cm ² , and a pulse duration of 30 ms.

The skin was observed with an anatomical microscope and a photograph was taken (Fig. 2). A cut was made perpendicular to the skin surface so as to pass through the hair follicle opening, and the cut surface was observed with an optical microscope (Fig. 3). Some samples were placed in a 10% buffered formalin solution and observed by routine histological examination (Fig. 4).

The skin was intact and undisturbed, except for punctuate dots at the hair follicle openings (Fig. 2). When cut and observed under a microscope, the presence of dark-colored nanoshells was observed in the hair follicle funnel and sebaceous glands (Fig. 3). No nanoshells were found in the epidermis or dermis around the hair follicles. Similarly, histological examination revealed thermal damage to the hair follicle funnel and sebaceous glands (Fig. 4). There was little or no damage to the epidermis or dermis around the hair follicles.

In one alternative embodiment, the method employs an ultrasonic horn used for immersion ultrasonic waves, where the peak-to-peak amplitude displacement of the ultrasonic horn surface is in the range of 0.5-30 microns.

In yet another embodiment, the submicron particle size is selected to pass through the hair follicle and enter the sebaceous glands of the hair follicle. In one embodiment, the hair follicle is a terminal hair follicle. In another embodiment, the hair follicle is a vellus hair follicle. In yet another embodiment, the hair follicles are sebaceous hair follicles. In yet another embodiment of the method described herein, the submicron particle size is from about 0.01 micron to about 1.0 micron. In yet another exemplary practice, submicron particle sizes range from about 0.05 micron to about 0.25 micron.

Example 5: Ultrasonic Accelerated Delivery A 300 Vp-p sine wave from a waveform generator and amplifier was used to drive a Mackeyville, PA APC International converter with a signal source impedance of 500 Ω. A 250 OD formulation (F78, Sebacia, Inc.) containing a 150 nm diameter silica core: gold shell was topically applied to the skin of depilated pig ears. After that, the upper surface was wiped and laser irradiation was performed with a Lumenis Lightsheer at 800 nm. The skin temperature was confirmed after the application of ultrasonic waves, but did not exceed 41 ° C.

Significant accumulation of nanoshells was observed in the hair follicles (Fig. 5). It was cut vertically so as to pass through the hair follicles, and the cut surface was observed under a microscope. An exemplary hair follicle is shown in FIG. Significant accumulation of nanoshells was noted inside and outside the funnel. The histological analysis of the sample is shown in FIG. Local heat damage to the hair follicles, including heat damage to the sebaceous glands, is observed (Fig. 7).

Example 6: Human clinical efficacy demonstrated in back acne In a clinical trial of back acne, the efficacy of laser treatment after topical delivery of nanoshells was evaluated. Nanoshells were topically applied to the back of each subject and laser treatment was initiated as described above. This treatment plan was performed twice for each subject. Results were evaluated 12 weeks after the second treatment. Efficacy was determined by the number of weighted inflammatory lesions. The results are shown in FIG. This study of the back acne study shows that the treatment plan was clinically effective.

Example 7: Human clinical efficacy demonstrated with sebaceous gland injury An IRB-approved human clinical trial was conducted in 17 subjects (6 males, 11 females) with acne. Subject ages ranged from 18 to 40 years (24 years on average) with phototypes I to IV. Treatment was performed on an area of 1 square inch (sebaceous hair follicles) behind the ears. After delivery of the nanoshell, laser treatment was performed and the laser was adjusted to the absorption peak of the nanoshell (40-50 J / cm2, 30 ms, 9 × 9 mm, Light Sheer (800 nm)). Therapeutic efficacy was histologically evaluated on 31 biopsies and 4-7 hair follicles were present on each biopsy. A 4 mm punch biopsy was performed, sliced continuously, and damage to the sebaceous hair follicles was visualized by H & E staining. There was very little pain, erythema, and edema. Local damage was observed in about 60% of the sebaceous hair follicles. Destruction of the entire sebaceous gland was observed in some specimens. The average depth of thermal damage in the hair follicles was 0.47 mm (maximum 1.43 mm). No incidental damage to the epidermis or dermis was observed. In-vivo histological studies observed damage to the funnel, hair ridges and sebaceous glands after treatment.

Example 8: Ultrasound-Promoted Delivery of Photodynamic Therapy (PDT) with Aminolevulinic Acid (ALA) In an ultrasonic experiment, hair follicles have access to deliver light-absorbing material rather than the stratum corneum. Was easy. The reason for this is considered to be the difference between the transport rate into the stratum corneum and the transport rate into the hair follicle. This difference can be used to facilitate selective delivery of relatively small molecules. This method can be used for chromophores in photothermal therapy schemes, or for photodynamic therapy with compounds or prodrugs that produce photodynamic effects. For example, conventional acne therapy, including ALA-PDT treatment, requires a long incubation time (about 3-4 hours) to deliver enough ALA to the sebaceous glands to achieve the desired clinical efficacy. do.

The result of this treatment is significant adverse side effects, including crusting of the epidermis, pain, and persistent redness. Such long incubation times deliver ALA to non-target areas of the epidermis and dermis. Ultrasound-assisted delivery can be achieved without such long incubation times, yet sufficient concentrations are achieved for the target funnel sebaceous system. ALA is rarely delivered to the non-target epidermis and dermis because ultrasonic delivery eliminates long incubation times. After ultrasonic delivery, the ALA preparation can be removed from the skin surface. Light irradiation is performed after a sufficient amount of time has passed to ensure that the concentration of the photoactive material within the target volume has reached a sufficient level. With photothermal treatment, pulsed laser irradiation can be initiated immediately after delivery.

In another embodiment, the material (compound) of interest is bound to the microparticles and delivered to the target volume. Light irradiation can be used to dissociate the material and cause its diffusion and subsequent effects. The formation of cavitation bubbles is facilitated by the presence of "seeded" nanoparticles in bubble formation. Delivery can also be facilitated by the use of volatile components such as ethanol.

Example 9: Formulation Various nanoshell preparations were tested on an ex vivo skin model. The test ingredient was designed to improve delivery into the hair follicle. The pharmaceutical constituents included surfactants such as ethanol, isopropyl alcohol, propylene glycol and polysorbate 80, phosphoripon 90, polyethylene glycol 400 and isopropyl adipate. The compatibility of these with each other was tested. Three types were identified: hydrophilic, lipophilic and liposomal. The absorption coefficient of the pharmaceutical product is suggested to be in the range of ^{10-1,000 cm-1.} The in vivo pig skin model was tested for the four formulations of the examples, and the compositions are shown in Table 3 below, showing the four formulations tested in the human back acne test.

Other Embodiments From the above description, it will be clear that the invention may be modified and modified such that the invention described herein is adopted for various uses and conditions. Such embodiments also fall within the scope of the following claims. The listing of elements in any definition of a variable herein includes the definition of a variable as any single element or combination (or partial combination) of enumerated elements. The description of embodiments herein includes embodiments as any single embodiment or in combination with any other embodiment or a portion thereof.

Incorporated by Reference This application relates to the subject matter described in U.S. Patent Application No. 12 / 787,655, U.S. Patent Application Publication No. 2012/0059307, and U.S. Patent No. 6,183,773. Each of these documents, including the objects to be obtained, is incorporated herein by reference in its entirety. All patents and publications described herein are incorporated herein by reference to the extent that each individual patent or publication is clearly and individually indicated by reference.

Claims (8)

A composition comprising plasmon gold nanoshells for treating or alleviating hair follicular skin disorders or permanent hair loss in a subject.
The plasmon gold nanoshell consists of a silica core about 120 nm in diameter and a gold shell about 15 nm thick , coated with PEG , present in an effective amount to induce local heating, and pharmaceutically. Or dispersed in a carrier that is acceptable as a cosmetic
The plasmon gold nanoshell has an absorption peak at a wavelength of 700 to 1,100 nm.
The composition is applied topically to the surface of the skin and
The plasmon gold nanoshell is applied to one or more parts selected from the group consisting of skin hair follicles, sebaceous glands, sebaceous gland ducts, and funnels with mechanical agitation, vibration, acoustic vibration, ultrasonic waves, suction and pressurization. And delivered by one or more techniques selected from the group consisting of the generation of microjets.
The plasmon gold nanoshells are removed from the subject's skin surface and
The plasmon gold nanoshell is exposed to externally applied near-infrared light to produce surface plasmons, whereby the plasmon gold nanoshell is heated to at least one selected from the group consisting of skin follicles and sebaceous glands. Heat damage or more parts,
The near-infrared light is near-infrared light having a wavelength that is preferentially absorbed by the plasmon gold nanoshell, and the plasmon gold nanoshell subsequently generates heat. The composition according to claim 1, wherein the composition improves the appearance of oily skin. The composition according to claim 1, wherein the composition improves the appearance of enlarged skin pores. The composition according to claim 1, wherein the hair to be depilated is a hair having a light pigment or a fine hair. The composition according to claim 1, wherein the skin is prepared by one or more treatments selected from the group consisting of heating, removal of hair follicle contents, and hair removal before the composition is applied. .. The composition of claim 1, wherein the skin is heated to a temperature of 40-44 ° C. The composition of claim 1, wherein the plasmon gold nanoshells are delivered by ultrasound with a frequency of 20 kHz to 500 kHz. The composition of claim 1, wherein the plasmon gold nanoshells are delivered in bubbles of approximately the same size as the ultrasonically induced hair follicle pores.

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